ABSTRACT Down syndrome (DS, trisomy 21) is the most common genetic cause of intellectual and developmental disability (IDD), but the cellular and molecular abnormalities that contribute to specific cognitive deficits are not well defined. Although DS individuals all have the same genetic cause of intellectual disability (trisomy 21), there is considerable variability in cognitive function across the patient population. In addition, while decades of data indicate that cortical interneurons are a vulnerable neuronal population in human DS and that their perturbation may be linked to altered cognitive function in DS patients, there is very limited data regarding how altered interneuron characteristics and dysfunction contribute to DS. Here, to address these challenges, we propose to build patient-derived induced pluripotent stem cell (iPSC) models from deeply phenotyped DS individuals who have been stratified based on cognitive ability (Aim 1). These models will provide a valuable resource for the DS research community, and will be used for cross-site replication of phenotypes and data meta-analyses conducted by the Cellular Modeling Units of two Intellectual and Developmental Disabilities Research Centers (IDDRCs), enhancing rigor and reproducibility of IDD cellular modeling across the network. In Aims 2 and 3, we will identify cellular and molecular signatures that reflect differences in cognitive ability: interneurons differentiated from these DS patient iPSCs will be analyzed for specific cellular defects, as well as through exploratory transcriptomic analysis, to identify cellular phenotypes and molecular signatures that distinguish DS individuals with high versus low cognitive functioning. Results from these experiments will define patient-relevant contributors to affectation that can be exploited in future projects to identify potential therapeutic targets for DS. This work integrates major directives of the IDDRC@WUSTL parent U54 grant in elucidation of intermediate phenotypes for IDDs, functional genomic discovery of convergent pathogenic mechanisms, and building of capacity for cellular modeling of IDDs, both at the IDDRC@WUSTL and throughout the IDDRC network. This collaboration also contributes to ongoing cross-IDDRC initiatives, led by these co-Investigators, to build shared cellular modeling resources for IDD research, including cross-IDDRC calibrated methods and benchmarks, new IDD models, and IDDRC-supported bio- and data-repositories for IDD cellular models. These initiatives will build capacity for IDD resource sharing and meta-analysis of data among IDDRC investigators throughout the network, enhancing the impact of this and other research projects, and will facilitate identification of convergent intermediate phenotypes, pathways, and molecular targets across different IDD models. These models provide a renewable, sharable resource, whereby the altered processes, pathways, and targets that are identified in this project can serve as a basis for future work using these models in combination with chemical and molecular screening to identify potential interventions.